ES2786306T3 - Improved compositions and methods comprising resveratrol - Google Patents

Abstract

Method of synthesis of a resveratrol salicylate, the method comprising the steps of: (a) activating resveratrol in the presence of a first solvent to produce activated resveratrol; (b) activating salicylic acid in the presence of a second solvent to produce activated salicylic acid; and (c) combining activated resveratrol and activated salicylic acid to produce a resveratrol salicylate mixture; wherein the resveratrol is activated by treatment with the first chosen solvent of 1,8-diazabicycloundec-7-ene (DBU); 1,5-diazabicyclo [4.3.0] non-5-ene (DBN); triethylamine (TEA); 2,6-di-tert-butylpyridine; phosphazene bases (t-Bu-P4, BEMP); Hünig's base (diisopropylethylamine, DIPEA); and 2,2,6,6-tetramethylpiperidine (TMP), and wherein salicylic acid is activated by treatment with any of the following: i) a carbodiimide chosen from N, N'-dicyclohexylcarbodiimide (DCC); N, N'-diisopropylcarbodiimide (DIC); N-cyclohexyl-N '- (2-morpholinoethyl) carbodiimide metho-p-toluenesulfonate (CMC); 1-tert-butyl-3-20 ethylcarbodiimide; 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC); N, N'-di-tert-butylcarbodiimide; N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide; or 1,3-di-p-tolylcarbodiimide; ii) a diimidazole selected from 1,1'-carbonyldiimidazole; 1,1'-thiocarbonyldiimidazole; or 1,1'-oxalyldiimidazole; or iii) a uronium or phosphonium reagent, selected from O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate; (7-Azabenzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate; (Benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate; N, N, N ', N'-tetramethyl-O- (N-succinimidyl) uronium tetrafluoroborate (TSTU); 1- [bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate (HATU); N, N, N ', N'-tetramethyl-O- (1H-benzotriazol-1-yl) uronium hexafluorophosphate (HBTU); or (1-cyano-2-ethoxy-2-oxoethylideneaminooxy) dimethylaminomorpholinocarbenium hexafluorophosphate (COMU).

Description

DESCRIPTION

Improved compositions and methods comprising resveratrol

Background

The present technology relates to the synthesis of resveratrol compositions, in particular resveratrol salicylates, and to cosmetic and pharmaceutical compositions comprising the same.

Resveratrol (3,4 ', 5-trihydroxy-trans-stilbene) is a polyphenol that occurs naturally in at least 72 species of plants. It is a powerful antioxidant that is superior to vitamins C and E as well as propyl gallate. It is also present in nature in the cis form , and is often produced as polidatin glycoside (piceid).

Attempts have been made to incorporate resveratrol and compounds comprising resveratrol into cosmetic and pharmaceutical compositions. However, its relative instability continues to present challenges. Thus, there is a need for improved methods for synthesizing resveratrol-containing compounds, as well as compositions comprising such compounds. For example, document US2013338120 describes aspirin derivatives useful to prevent and / or treat cancer. These compounds may be useful for the prevention and / or treatment of cancers that affect the digestive tract, such as colorectal cancer. WO2004000302 describes resveratrol analogs of the formula given below:

where R, R ¹ , R ^2, and R ³ are:

1. R = OH, R1 = R2 = R3 = H;

2. R = OH, R ¹ = Br, R ² = R ³ = H;

3. R = R1 = OH, R2 = R3 = H;

4. R = R1 = R3 = H, R2 = 3,4,5-trihydroxybenzoyl;

5. R = R ¹ = H, R2 = R3 = 3,4,5-trihydroxybenzoyl;

6. R = R1 = R3 = H, R2 = 3,4-dihydroxycinnamoyl;

7. R = R1 = R3 = H, R2 = 3,4,5-trihydroxycinnamoyl;

8. R = R1 = Rs = H, R2 = -CH2CH2N (CH3) 2;

9. R = R1 = R3 = H, R2 = -COCH2NH2.HCl.

These compounds showed antioxidant properties and are useful in the food industry and in cosmetic products. The compounds can be used in a pharmaceutical composition as an antioxidant or free radical scavenger. US2009068132 describes cosmetic compositions containing resveratrol ferulate in a topically acceptable carrier. Such compositions are effective for skin whitening and anti-aging applications. US8575217 describes methods for treating metabolic disorders with compounds that are conjugated. Conjugates are composed of salicylic acid, triflusal, diflunisal, salsalate, IMD-0354, ibuprofen, diclofenac, licofelone, or HTB, and one or more antioxidants.

Summary of technology released

In a preferred embodiment, the present technology refers to a method of synthesis of a resveratrol salicylate as defined in claim 1, the method comprising the steps of: (a) activating resveratrol in the presence of a first solvent to produce resveratrol activated; (b) activating salicylic acid in the presence of a second solvent to produce activated salicylic acid; and (c) combining activated resveratrol and salicylic acid activated to produce a resveratrol salicylate mixture.

In certain embodiments, the present technology refers to a method of synthesis of a mixture of mono, di, tri or polysubstituted resveratrol salicylates as defined in claim 5, the method comprising the steps of: (a) combining salicylic acid activated with activated resveratrol in one or more solvents; and (b) controlling the ratio or percentage of di, tri, or polysubstituted resveratrol by controlling the molar ratio of activated salicylic acid to activated resveratrol.

In a preferred embodiment, the present technology relates to a mixture of resveratrol salicylates, the mixture comprising (a) monosubstituted resveratrol salicylates; and (b) di and trisubstituted resveratrol salicylates. In certain embodiments, the mixture may comprise any two or more of the following: (a) monosubstituted resveratrol salicylates; (b) disubstituted resveratrol salicylates; (c) trisubstituted resveratrol salicylates; or (d) polysubstituted salicylates.

In certain embodiments, the present technology relates to a method of synthesizing a mixture of mono-, di- or trisubstituted resveratrol as defined in claim 8, the method comprising the steps of: (a) combining activated salicylic acid with activated resveratrol in one or more solvents; Y

(b) controlling the ratio of di, tri, or polysubstituted resveratrol salicylates by varying the molar ratio of activated salicylic acid to activated resveratrol.

In a preferred embodiment, the present technology refers to a method of synthesis of a resveratrol salicylate as defined in claim 10, the method comprising the steps of:

(a) combining resveratrol and salicylic acid with a solvent to provide a solution comprising resveratrol and salicylic acid; Y

(b) contacting the solution with an activator to provide a solution comprising activated salicylic acid.

Brief description of the figures

Figures 1-6 show additional details regarding various embodiments of the technology discussed herein, including Examples 2 and 3.

Figures 7-8 show additional details and reaction steps pertaining to various embodiments of the technology discussed herein, including Example 1.

Figure 9 shows chromatography data of a crude reaction mixture according to various embodiments herein.

Figures 10-11 show reaction steps relating to the synthesis of mono, di, tri, and polysubstituted salicylates according to various embodiments herein.

Figure 12 shows chromatography data of a mixture according to various embodiments herein. Figure 13 shows reaction steps relating to the synthesis of frans-resveratrol and sodium salicylate according to various embodiments herein.

Figure 14 shows chromatography data of a mixture according to various embodiments herein. Figure 15 shows reaction steps relating to the synthesis according to various embodiments herein.

Figure 16 shows chromatography data of a mixture according to various embodiments herein. Figure 17 shows reaction steps relating to synthesis according to various embodiments herein.

Figure 18 shows chromatography data of mixtures according to various embodiments herein. Figure 19 shows the mass spectroscopy analysis of a mixture according to various embodiments herein.

Figure 20 shows chromatography data of a crude reaction mixture according to various embodiments in the present document.

Figures 21-26 show results of assay data determining the antioxidant activity of various mixtures and reaction products according to the technology herein.

Detailed description

Resveratrol is highly unstable; it is labile under both strongly acidic and strongly basic conditions. It undergoes extensive oxidation in basic solutions. When irradiated with UV light having a wavelength in the range of 350 to 360 nm, trans-resveratrol photoisomerizes to give the cis isomer . C / s-resveratrol is less stable and less biologically active. The presence of multiple hydroxyl (-OH) functional groups in its stilbene backbone predisposes resveratrol to a variety of chemical reactions such as electrophilic aromatic substitution.

A novel synthetic approach to converting resveratrol to a mixture of resveratrol salicylates has been developed herein. In certain embodiments, the methods herein produce not only monosubstituted resveratrol salicylate, but also disubstituted, trisubstituted, and polysubstituted resveratrol salicylate, including forms that are mono, di, tri, and polysubstituted (i.e., substituted with more than 3) with polysalicylate residues of varying size.

In certain embodiments, the methods comprise the following steps: (1) obtaining resveratrol, subjecting it to an activator and a solvent to produce activated resveratrol; (2) obtain salicylic acid, subject it to activator and solvent to produce activated salicylate.

Useful salicylic acid activators are carbodiimides chosen from: N, N'-dicyclohexylcarbodiimide (DCC); N, N'-diisopropylcarbodiimide (DIC); N-cyclohexyl-N '- (2-morpholinoethyl) carbodiimide metho-p-toluenesulfonate (CMC); 1-tertbutyl-3-ethylcarbodiimide; 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC); N, N'-di-tert-butylcarbodiimide; N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide; or 1,3-di-p-tolylcarbodiimide; diimidazoles selected from 1,1'-carbonyldiimidazole; 1,1'-thiocarbonyldiimidazole; or 1,1'-oxalyldiimidazole; and uronium or phosphonium reagents selected from O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate; (7-Azabenzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate; (Benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate; N, N, N ', N'-tetramethyl-O- (N-succinimidyl) uronium tetrafluoroborate (TSTU); 1- [bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate (HATU); N, N, N ', N'-tetramethyl-O- (1H-benzotriazol-1-yl) uronium hexafluorophosphate (HBTU); or (1-cyano-2-ethoxy-2-oxoethylideneaminooxy) dimethylaminomorpholinocarbenium hexafluorophosphate (COMU).

The resveratrol activators are chosen from the following: 1,8-diazabicycloundec-7-ene (DBU); 1,5-diazabicyclo [4.3.0] non-5-ene (DBN); triethylamine (TEA); 2,6-di-tert-butylpyridine; phosphazene bases (t-Bu-P4, BEMP); Hünig's base (diisopropylethylamine, DIPEA); or 2,2,6,6-tetramethylpiperidine (TMP).

Examples of useful solvents include, but are not limited to, the following: polar aprotic solvents, eg, acetonitrile; dimethylsulfoxide (D ^ms O); hexamethylphosphoramide (HMPA); 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone (DMPU); 1,3-dimethyl-2-imidazolidinone (DMI); dimethylformamide (DMF); or 1-methyl-2-pyrrolidinone (NMP) or dimethylaminopyridine (DMAP).

In certain embodiments, activation can be carried out separately for resveratrol and salicylic acid. In a non-limiting example, resveratrol can be activated by treatment with a resveratrol activator in a solvent. Similarly, salicylic acid can be activated by treatment with a solvent using an excess of a salicylic activator. In various embodiments, the coupling reaction can then be run in a 1.5: 1 (v / v) mixture of the two solvents. In other examples, carbodiimides can be used for salicylic acid activation, alone or in combination with other molecules such as N-hydroxysuccinimide (NHS).

Example 1

In a non-limiting example, activation of resveratrol runs for approximately 10 min at room temperature. Since the salicylic acid activation is an exothermic process, the reaction flask can be kept in a cooling bath while the salicylic acid activator is added in portions over a period of about 1 to about 15 minutes, depending on the reaction scale. In this example, salicylic acid was activated with N, N'-diisopropylcarbodiimide (DIC) or dicyclohexylcarbodiimide (DCC). After the addition of salicylic acid activator is complete, the cooling bath can (but need not) be removed. This activation can also run for about 30 to about 90 minutes, or longer. Resveratrol can be activated with Hünig's base. The reaction mixture containing activated resveratrol can then be combined with activated salicylic acid. The resulting mixture can be stirred at room temperature for, in various embodiments, up to about 72 hours, or about 1, about 2, or about 3 days.

As demonstrated herein, the distribution of resveratrol salicylate products is dependent on the molar ratio of activated salicylic acid to activated resveratrol, favoring a higher ratio to more substituted product. Thus, in certain embodiments, the resveratrol salicylate mixture comprises mono-, di- and trisubstituted resveratrol salicylates; The ratios of the various substituted resveratrol salicylates in the mixture can be controlled by varying the molar ratio of activated salicylic acid to activated resveratrol, generally leading to higher ratios of activated salicylic acid to more highly substituted products. Thus, in certain embodiments, the resveratrol salicylate mixture comprises mono-, di-, and trisubstituted resveratrol, and other polymeric salicylates at one or more hydroxyl groups of resveratrol; in other words, one or more salicylic acid molecules conjugated to any one or more / all of the hydroxyls in resveratrol. Thus, in certain embodiments, an investigator can optimize or control the relative proportions of mono, di, tri, and polysubstituted resveratrol with salicylate by varying or controlling the molar ratios of activated salicylic acid and activated resveratrol. For example, the investigator may choose to increase the amount of monosubstituted resveratrol salicylates by decreasing the molar ratio of activated salicylic acid to activated resveratrol; instead, if you want a higher proportion of di, tri, or polysalicylate substituted resveratrol, you can optimize these amounts by increasing the molar ratio of activated salicylic acid to activated resveratrol. In fact, in certain embodiments, the researcher may decide that maximizing the proportion of the highest substitute end product is a more beneficial way of employing the methods herein.

Example 2

In another non-limiting example, the process for synthesizing resveratrol salicylates includes a two-part double activation process. Salicylic acid is converted to a salicylic acid solution with the addition of dimethylformamide, and then activated with diisopropylcarbodiimide (DIC) to provide activated salicylic acid, a highly exothermic process that requires cooling. An example schematic is shown in Figure 1. Resveratrol is converted to a resveratrol solution with the addition of dimethylsulfoxide, and then activated with diisopropylethylamine to provide activated resveratrol. The activated resveratrol and activated salicylic acid are then combined, and the reaction is allowed to proceed approximately 96 hours at room temperature. The precipitated solids are washed with ultrapure water, and solubilized with ethyl acetate; as shown, for example, in Figure 2. In addition, the precipitated solid product was solubilized with ethyl acetate to produce a solution containing the product. The solution was mixed vigorously in water to remove impurities, then collected using a separatory funnel. Then the solvent was removed with a vacuum rotary evaporator, and the dry solids were manually removed from the flask, for example, as shown in Figure 3.

Example 3

In another non-limiting example, the following was observed: In certain embodiments, the present technology relates to a single solvent, a single activation reaction of salicylic acid, resveratrol, and acetonitrile with DCC. An example diagram is shown in Figure 4. Such a reaction differs from other embodiments of the technology in that it relates to a two-part double activation procedure that requires further cleaning and purification (eg, Example 2). In this example, the resveratrol and salicylic acid are together in a solution with acetonitrile. The solution is activated with dicyclohexylcarbodiimide (DCC) by controlled addition to provide activated resveratrol and salicylic acid (a highly exothermic procedure that requires cooling). This solution is maintained at about 10 to about 85 ° C for about 24 hours, after which time the reaction mixture is filtered to remove solids, including solids including dicyclohexylurea. The supernatant is collected and dried using an evaporator or drier to concentrate the desired solids while maintaining solubility. A small volume of water can be added to neutralize any activated DCC, and the material is dried to give the final product, for example, as shown in Figure 5.

Advantages of this example include the following: only one trigger is required; the reaction can be carried out in a single reactor and therefore dangers and transfer time delays of activated SA and resveratrol can be avoided; and there are significant cost savings associated with using only one reactor and only one activator. Certain embodiments according to this example are shown in Figures 4 to 6.

In certain embodiments, the present technology relates to a method of synthesizing a mixture of mono, di, tri, and polysubstituted resveratrol salicylates, the method comprising the steps of: (a) combining activated salicylic acid with activated resveratrol in one or more solvents; and (b) controlling the ratio of substituted resveratrol salicylates by varying the molar ratio of activated salicylic acid to activated resveratrol. Certain embodiments of the present technology would also contemplate the step of controlling the hydrolysis of the polysubstituted resveratrol to give a desired distribution of mono-, di-, tri- and polysalicylate modified resveratrol.

In the examples herein, the differently substituted compounds could be separated in a predictable manner. Both reaction work-up procedures and sophisticated HPLC-based purification and isolation protocols were developed, which allowed for the separation and isolation of specifically substituted resveratrol salicylates. Therefore, a reliable chemistry has been developed to synthesize salicylates. according to present technology. Chromatographic methods have been established for the analysis of the reaction and the isolation of the product. The composition and identity of the reaction products were established by limited and exhaustive hydrolysis and corroborated by mass spectroscopy, as shown, for example, in Figures 7 to 24.

In particular, Figure 21 shows absorption results versus wavelength with a DPPH assay, indicating that the compositions herein show high levels of antioxidant activity. In addition, Figures 22-24 illustrate, among other things, an increase in free resveratrol and monosubstituted resveratrol salicylate, an overall decrease in complexity, and an apparent loss of all other ester derivatives. In certain embodiments, reaction conditions can be optimized to generate desired product distributions, and evaluation of the antioxidant properties of resveratrol salicylates can be carried out by HPLC DPPH assay.

Example 4

The cytotoxicity of the compositions was measured herein. Dermal fibroblasts or human epidermal keratinocytes were seeded in 96-well plates and grown to confluence. Duplicate wells were fed with medium containing varying concentrations of resveratrol salicylate mixture that was solubilized in DMSO. The DMSO concentration was kept constant (0.5%) in all wells including the control wells that did not include resveratrol salicylate.

After contact with the resveratrol salicylate for either 17 or 65 hours, the media was removed and the cells were incubated for 1 hour in buffered saline containing 42 pM resazurin. The fluorescence (ex. 530 / em. 580) of resorufin (resazurin reduction product) was measured after 1 hour. All data was normalized to the fluorescence of the control wells, which represented 100% viability. The degree of resazurin reduction is a measure of total mitochondrial metabolic activity, and is proportional to the number of cells. The results are shown graphically in Figures 25 and 26, and show that resveratrol salicylate was only slightly toxic to both fibroblasts and keratinocytes at the highest concentration tested of 0.016%. This caused a decrease in viability of approximately 10% after a 65 hour exposure. However, the concentration was not toxic after a 17 hour exposure. All lower concentrations were non-toxic at both time points. As used herein, "non-toxic" means showing cytotoxicity of less than about 5%. In certain embodiments, the resulting resveratrol salicylate mixture, when contacted with fibroblasts or keratinocytes, results in a cytotoxicity of less than about 10% after 17 hours of contact. In certain embodiments, the mixtures herein have the additional feature that they result in a cytotoxicity of less than about 20%, less than about 10%, or less than about 5% after 65 hours of contact with fibroblasts. or keratinocytes.

Figures 6-8, 10, 11, 13, 15 and 17 show the synthesis of resveratrol derivatives as carried out according to certain embodiments herein. Figures 9, 12, 14, 16, 18 and 20 show the analysis results of some example mixtures that were created and tested, many of which show identifying peaks at various times. Figure 19 shows a mass spectroscopy analysis, with a major product peak at 15.8 minutes. As can be seen from the figures, it has been established herein that there are methods for predicting and quantifying desired results, in terms of distribution of resveratrol salicylates by desired degrees of substitution, and that the methods result in stable and low-grade products. high quality that have many industrial and commercial applications.

Unlike the present technology, the Maes publication (US Patent Application Publication No. 2012/0288460) does not describe the actual synthesis of resveratrol salicylates. Instead, it provides the synthetic procedure for making resveratrol triphosphates, as set forth in WO 2006 / 029484A1. The work teaches the treatment of resveratrol under basic conditions with dibenzyl phosphate in the presence of dimethylaminopyridine (DMAP). Although this procedure might be acceptable to make resveratrol triphosphate, it cannot be used to make resveratrol salicylates. An analogous approach with methyl salicylate was attempted and resulted in no product. Furthermore, the described method is unfeasible since it uses carbon tetrachloride as solvent. Carbon tetrachloride is one of the hepatotoxins and one of the most powerful inducers of liver cancer.

An alternative approach, mentioned in US Patent No. 6,572,882, involves the synthesis of carboxylic acid esters of resveratrol by the Schotten-Baumann reaction. The procedure is based on the treatment of resveratrol under basic conditions with commercially available carboxylic acid chlorides. Although it is possible for simple carboxylic acids, the method cannot be used to make salicylates, as salicylic acid chloride cannot be prepared due to the presence of the interfering ortho-hydroxyl group.

In summary, the present technology is far superior for many reasons, including, but not limited to, the following: the methods herein are different from those known in the art; methods Resveratrol salicylates are herein generated as products, and these products can be confirmed (presence and identity) by both spectral and chemical analysis; and the methods herein can be used to obtain many different resveratrol salicylates, including, but not limited to, resveratrol polysalicylates. The subsequent synthesis approaches and purification methods used herein can avoid toxic solvents and mutagens, and are highly susceptible to upscaling.

Although the present technology has been described in connection with particular embodiments thereof, these embodiments and examples are merely exemplary and are not intended to be limiting. It will be apparent to one of ordinary skill in the art that aspects of the technology, as described above, can have many applications.

Claims (8)

1. Synthesis method of a resveratrol salicylate, the method comprising the steps of: (a) activating resveratrol in the presence of a first solvent to produce activated resveratrol; (b) activating salicylic acid in the presence of a second solvent to produce activated salicylic acid; and (c) combining activated resveratrol and activated salicylic acid to produce a resveratrol salicylate mixture; wherein the resveratrol is activated by treatment with the first chosen solvent of 1,8-diazabicycloundec-7-ene (DBU); 1,5-diazabicyclo [4.3.0] non-5-ene (DBN); triethylamine (TEA); 2,6-di-tertbutylpyridine; phosphazene bases (t-Bu-P4, BEMP); Hünig's base (diisopropylethylamine, DIPEA); and 2,2,6,6 tetramethylpiperidine (TMP), and in which salicylic acid is activated by treatment with any of the following: i) a carbodiimide chosen from N, N'-dicyclohexylcarbodiimide (DCC); N, N'-diisopropylcarbodiimide (DIC); N-cyclohexyl-N '- (2-morpholinoethyl) carbodiimide metho-p-toluenesulfonate (CMC); 1-tert-butyl-3-ethylcarbodiimide; 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC); N, N'-di-tert-butylcarbodiimide; N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide; or 1,3-di-p-tolylcarbodiimide; ii) a diimidazole selected from 1,1'-carbonyldiimidazole; 1,1'-thiocarbonyldiimidazole; or 1,1'-oxalyldiimidazole; or iii) a uronium or phosphonium reagent, selected from O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate; (7-Azabenzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate; (Benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate; N, N, N ', N'-tetramethyl-O- (N-succinimidyl) uronium tetrafluoroborate (TSTU); 1- [bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate (hAt U); N, N, N ', N'-tetramethyl-O- (1H-benzotriazol-1-yl) uronium hexafluorophosphate (HBTU); or (1-cyano-2-ethoxy-2-oxoethylideneaminooxy) dimethylaminomorpholinocarbenium hexafluorophosphate (COMU). A method according to claim 1, wherein the resveratrol salicylate mixture comprises mono-, di- and trisubstituted resveratrol salicylates at one or more hydroxyls of resveratrol. A method according to claim 1, wherein one or both of the first solvent or the second solvent is / is a polar aprotic solvent selected from acetonitrile; dimethylsulfoxide (DMSO); hexamethylphosphoramide (HMPA); 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone (DMPU); 1,3-dimethyl-2-imidazolidinone (DMI); dimethylformamide (DMF) or 1-methyl-2-pyrrolidinone (NMP). 4. The method according to claim 1, wherein the salicylic acid is activated by treatment with a carbodiimide of (i) in combination with N-hydroxysuccinimide (NHS). Method according to claim 1 of synthesis of a mixture of mono, di, tri or polysubstituted resveratrol salicylates, the method comprising the step of varying the ratio of di, tri or polysubstituted resveratrol salicylates by increasing the molar ratio of activated resveratrol with relative to activated salicylic acid. 6. Mixture of resveratrol salicylates, the mixture comprising any two or more of the following: (a) monosubstituted resveratrol salicylates; (b) disubstituted resveratrol salicylates; (c) trisubstituted resveratrol salicylates; or (d) polysubstituted salicylates. 7. A mixture of resveratrol salicylates according to claim 6, the mixture comprising: (a) monosubstituted resveratrol salicylates; Y (b) di and trisubstituted resveratrol salicylates. Method according to claim 1 of synthesis of a mixture of mono, di, tri or polysubstituted resveratrol salicylates, the method comprising the step of controlling the ratio of di, tri or polysubstituted resveratrol salicylates by varying the molar ratio of activated salicylic acid with respect to activated resveratrol. The method of claim 8, further comprising the step of controlling the hydrolysis of the polysubstituted resveratrol to give a desired distribution of mono-, di-, tri- or polysalicylate modified resveratrol. Synthesis method of a resveratrol salicylate, the method comprising the steps of: (a) combining resveratrol and salicylic acid with a solvent to provide a solution comprising resveratrol and salicylic acid; Y (b) contacting the solution with an activator to provide a solution comprising activated salicylic acid; in which the trigger is chosen from the following: (i) a carbodiimide chosen from N, N'-dicyclohexylcarbodiimide (DCC); N, N'-diisopropylcarbodiimide (DIC); N-cyclohexyl-N '- (2-morpholinoethyl) carbodiimide metho-p-toluenesulfonate (CMC); 1-tert-butyl-3-ethylcarbodiimide; 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC); N, N'-di-tert-butylcarbodiimide; N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide; or 1,3-di-p-tolylcarbodiimide; (ii) a diimidazole selected from 1,1'-carbonyldiimidazole; 1,1'-thiocarbonyldiimidazole; or 1,1'-oxalyldiimidazole; or (iii) a uronium or phosphonium reagent, selected from: O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate; (7-Azabenzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate; (Benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate; N, N, N ', N'-tetramethyl-O- (N-succinimidyl) uronium tetrafluoroborate (TSTU); 1- [bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate (hAt U); N, N, N ', N'-tetramethyl-O- (1H-benzotriazol-1-yl) uronium hexafluorophosphate (HBTU); or (1-cyano-2-ethoxy-2-oxoethylideneaminooxy) dimethylaminomorpholinocarbenium hexafluorophosphate (COMU). Method according to claim 10, further comprising the step of: (c) drying the solution to produce a solid resveratrol salicylate. Method according to claim 10, in which the solvent is selected from acetonitrile; dimethylsulfoxide (DMSO); hexamethylphosphoramide (HMPA); 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone (DMPU); 1,3-dimethyl-2-imidazolidinone (DMI); dimethylformamide (DMF); 1-methyl-2-pyrrolidinone (NMP); and dimethylaminopyridine (DMAP).